Oleandrin

Oleandrin plant poisoning is common in children and the plant extract is used in Chinese medicines. The toxicity is due to oleandrin and the deglycosylated metabolite oleandrigenin. Bufalin and cinobufotalin (toad cardiac toxins) are also widely used in Chinese medicines like Chan SU, and Lu-Shen -WU. Severe toxicity from bufalin after consumption of toad soup has been reported. Taking advantage of structural similarities of these toxins with digitoxin, we demonstrated that these compounds can be rapidly detected in blood by the fluorescence polarization immunoassay for digitoxin. The cross reactivities of these compounds with digoxin assay were much lower. For example, when a drug free serum was supplemented with 10 ug/mL of oleandrin, we observed 127.7 ng/mL of digitoxin equivalent but only 2.4 ng/mL of digoxin equivalent concentration. Digibind neutralized all cardiac toxins studied as evidenced by significant fall of free concentrations. When aliquots of serum pool containing 50.0 ug/mL of oleandrin were supplemented with 0, 10.0, 25.0, 50.0, 100, and 200 ug/mL of digibind, the mean free concentrations were 30.6, 23.3, 16.0, 10.7, 7.8 and 5.5 ug/mL respectively. Similarly, with 50.0 ug/mL of oleandrigenin (total concentration: 36.2 ng/mL), the free concentration was 14.5 ng/mL digitoxin equivalent in the absence of digibind and 5.4 ng/mL in the presence of 200 microg/mL of digibind. In another specimen containing 500 ng/mL bufalin (total concentration: 156.9 ng/mL), the free concentration was 8.6 ng/mL in the absence of digibind and none detected in the presence of 100.0 ug/mL digibind. Because such neutralization may also occur in vivo, digibind may be useful in treating patients exposed to these toxins.

Considering the potential role of interleukin-8 (IL-8) in inflammation, angiogenesis, tumorogenesis, and metastasis, and the involvement of different cell types especially neutrophils and macrophages in those processes, the regulation of IL-8-mediated biological responses is important. In this report we provide evidences that oleandrin, a cardiac glycoside potentially inhibited IL-8-, formyl peptide (FMLP)-, EGF-, or nerve growth factor (NGF)-, but not IL-1- or TNF-induced NF-kappaB activation in macrophages. Oleandrin inhibited IL-8-, but not TNF-induced NF-kappaB-dependent genes expression. Oleandrin inhibited the binding of IL-8, EGF, or NGF, but not IL-1 or TNF. It decreased almost 79% IL-8 binding without altering affinity towards IL-8 receptors and this inhibition of IL-8 binding was observed in isolated membrane. The IL-8, anti-IL-8Rs antibodies, or protease inhibitors were unable to protect oleandrin-mediated inhibition of IL-8 binding. Phospholipids significantly protected oleandrin-mediated inhibition of IL-8 binding thereby restoring IL-8-induced NF-kappaB activation. Oleandrin altered the membrane fluidity as detected by microviscosity parameter and a decrease in diphenylhexatriene, a lipid binding fluorophore binding in a dose-dependent manner. Overall, our results suggest that oleandrin inhibits IL-8-mediated biological responses in diverse cell types by modulating IL-8Rs through altering membrane fluidity and microviscosity. The study might help to regulate IL-8-mediated biological responses involved in inflammation, metastasis, and neovascularization.

Oleander (Nerium oleander) poisoning is a common problem found in many parts of the world. The oleander toxicity is due to oleandrin and its aglycone metabolite oleandrigenin. Activated charcoal is a useful gastrointestinal decontamination agent that limits the absorption of ingested toxins. A relatively new clay product, Bio-Sponge, containing di-tri-octahedral smectite as the active ingredient, is also recommended for adsorbing bacterial toxins in the gastrointestinal tract. Bio-Sponge has been used to prevent gastrointestinal absorption of oleander toxins in livestock but the efficacy of activated charcoal and Bio-Sponge for adsorbing oleandrin and oleandrigenin has not yet been studied. An in vitro experiment to compare the efficacy of three commercially available adsorbents was performed. The adsorbents include Bio-Sponge, ToxiBan granules, and a generic grade activated charcoal. ToxiBan granules have the highest adsorptive capacity, followed by the generic grade activated charcoal, and finally, Bio-Sponge. Bio-Sponge did not adsorb oleandrin and oleandrigenin at concentrations that are expected to be present in the gastrointestinal tract of poisoned animals. On the basis of this in vitro study, products containing activated charcoal are more effective for binding oleander toxins and providing gastrointestinal decontamination than products containing di-tri-octahedral smectite. However, the ability of these adsorbents to alter the clinical outcome in oleander-poisoned animals or humans is yet to be evaluated.

Cardiac glycosides such as digitoxin and ouabain have previously been shown to be selectively cytotoxic to tumor as opposed to normal cells. Moreover, this class of agents has also been shown to act as potent radiosensitizers. In the present study we explored the relative radiosensitization potential of oleandrin, a cardiac glycoside contained within the plant extract known as Anvirzel that recently underwent a Phase I trial as a novel drug for anticancer therapy. The data show that oleandrin produces an enhancement of sensitivity of PC-3 human prostate cells to radiation; at a cell survival of 0.1, the enhancement factor was 1.32. The magnitude of radiosensitization depended on duration of exposure of cells to drug prior to radiation treatment. While a radiosensitizing effect of oleandrin was evident with only 1 hr of cell exposure to drug, the effect greatly increased with 24 hr oleandrin pretreatment. Susceptibility of PC-3 cells to oleandrin and radiation-induced apoptosis was dependent on activation of caspase-3. Activation was greatest when cells were exposed simultaneously to oleandrin and radiation. Inhibition of caspase-3 activation with Z-DEVD-FMK abrogated the oleandrin-induced enhancement of radiation response suggesting that both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 cell line.

Ceramide (N-acetyl-D-sphingosine), a second messenger for cell signaling, induces transcription factors, like nuclear factor-kappa B (NF-kappa B), and activator protein-1 (AP-1) and is involved in inflammation and apoptosis. Agents that can suppress these transcription factors may be able to block tumorigenesis and inflammation. Oleandrin (trans-3,4',5-trihydroxystilbene), a polyphenolic cardiac glycoside derived from the leaves of Nerium oleander, has been used in the treatment of cardiac abnormalities in Russia and China for years. We investigated the effect of oleandrin on NF-kappa B and AP-1 activation and apoptosis induced by ceramide. Oleandrin blocked ceramide-induced NF-kappa B activation. Oleandrin-mediated suppression of NF-kappa B was not restricted to human epithelial cells; it was also observed in human lymphoid, insect, and murine macrophage cells. The suppression of NF-kappa B coincided with suppression of AP-1. Ceramide-induced reactive intermediates generation, lipid peroxidation, cytotoxicity, caspase activation, and DNA fragmentation were potentiated by oleandrin. Oleandrin did not show its activity in primary cells. Oleandrin's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappa B and AP-1 and potentiation of apoptosis.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 730(SRC), determined from a structure estimation method(2), indicates that oleandrin is expected to have low mobility in soil(SRC). Volatilization of oleandrin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.1X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Oleandrin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.6X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A 90% removal of oleandrin in 50 days during aerobic composting in a turned pile(4) suggests that biodegradation may be a moderate environmental fate process in soil(SRC).

FIELD STUDY: California recycles 50% of previously disposed trash. Increased use of yardwastes and composts has raised concern about toxic materials in these products. Oleander is a toxic shrub common to CA landscapes and is frequently clipped and disposed of in greenwaste containers, resulting in concerns about the toxicity of oleander-contaminated yardwastes and composts from these wastes. Information about breakdown of oleandrin (one of the glycoside toxicants of oleander) during composting or the ability of plants to absorb this molecule has not been reported. In separate experiments, we documented the apparent first-order disappearance of oleandrin from composts of pure oleander, with a disappearance half-life of 15 d. Within 50 d, 90% of the oleandrin was removed during aerobic composting in a turned pile. In an amendment study with fresh uncomposted oleander, no oleandrin was detected in tomato and zuchinni fruit, snap beans, carrot tubers, or green lettuce. Oleandrin was found in red leaf lettuce growing in soils mulched with oleander, but oleandrin concentrations were near the detection limit of the assay. Soil from oleander mulched and amended plots contained low levels of oleandrin at the time of harvest.

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 730(SRC), determined from a structure estimation method(2), indicates that oleandrin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.1X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 22(SRC), from its log Kow of 2.53(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), oleandrin, which has an estimated vapor pressure of 3.6X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase oleandrin may be removed from the air by wet and dry deposition(SRC). Oleandrin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Oleandrin is a solid. It is a cardiac glycoside found in plants Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander). HUMAN EXPOSURE AND TOXICITY: Ingestion of either oleandrin results in nausea, vomiting, abdominal pain, diarrhea, dysrhythmias, and hyperkalemia. In poisoning by oleander, mydriasis characteristically accompanies vertigo, convulsions, coma, and bradycardia. Accidental ingestion can cause cardiac arrhythmias and even death. Several cases of fatal and non-fatal poisoning have been reported. ANIMAL STUDIES: Oleander intoxication should be a differential diagnosis for equids with colic in geographic areas where oleander is found, especially when azotemia or cardiac arrhythmias are detected concurrently. ECOTOXICITY STUDIES: For freshwater fish C. punctatus exposure to sub-lethal doses of oleandrin for 24 hr and 96 hr caused significant alteration in the level of total protein, total free amino acid, nucleic acid, glycogen, pyruvate, lactate and enzyme protease, phosphatases, alanine aminotransferase, aspartate aminotransferase and acetylcholinesterase activity in liver and muscle tissues.

Oleandrin likely exerts its toxic effects by inhibiting Na+,K+-ATPase. (A2831)

/AQUATIC SPECIES/ Active compound oleandrin extracted from Nerium indicum (Lal Kaner) leaf has potent piscicidal activity. The piscicidal activity of oleandrin on freshwater fish C. punctatus was both time and dose dependent. Exposure to sub-lethal doses of oleandrin for 24 hr and 96 hr to fish caused significant alteration in the level of total protein, total free amino acid, nucleic acid, glycogen, pyruvate, lactate and enzyme protease, phosphatases, alanine aminotransferase, aspartate aminotransferase and acetylcholinesterase activity in liver and muscle tissues. The alterations in all the above biochemical parameters were also significantly time and dose dependent. The results show a significant recovery in all the above biochemical parameters, in both liver and muscle tissues of fish after the 7th day of the withdrawal of treatment. Toxicity persistence test of oleandrin on juvenile Labeo rohita shows that fish seed of common culturing carp can be released into rearing ponds after three days of oleandrin treatment. It supports the view that the oleandrin is safer and may be useful substitute of other piscicides for removing the unwanted freshwater fishes from aquaculture ponds.

/OTHER TERRESTRIAL SPECIES/ Exposure to 40% and 80% of the 24 hr LC50 of the molluscicidal component of Abrus precatorius (abrin and glycyrrhizin), Argemone mexicana (protopine and sanguinarine) and Nerium indicum (oleandrin) caused a significant decrease in the levels of protein, free amino acid, DNA and RNA in the nervous tissue of Lymnaea acuminata. Except for glycyrrhizin, all the above molluscicides caused a significant reduction in phospholipid levels and a simultaneous increase in the rate of lipid peroxidation in the nervous tissue of treated snails.

Oleandrin occurs naturally in the leaves of Laurier rose (Nerium oleander L., (Apocynaceae))(1). Indian oleander (N. indicum) is an evergreen shrub or small tree which is cultivated worldwide. It has become naturalized in an area ranging from Mauritania, Morocco and Portugal. The plant is native to India, Bangladesh, Nepal, Myanmar and China(2).

Oleandrin was detected not quantified in the leaf of Nerium oleander (Apocynaceae), oleander(1).

The gastrointestinal effects can consist of nausea and vomiting, excess salivation, abdominal pain, diarrhea, and colic. Cardiac reactions consist of irregular heart rate, and extremities may become pale and cold due to poor or irregular circulation. Reactions to poisonings from this plant can also affect the central nervous system. These symptoms can include drowsiness, tremors or shaking of the muscles, seizures, collapse, and even coma that can lead to death. Oleander sap can cause skin irritations, severe eye inflammation and irritation, and allergy reactions characterized by dermatitis. (L1253)

Using a structure estimation method based on molecular connectivity indices(1), the Koc of oleandrin can be estimated to be 730(SRC). According to a classification scheme(2), this estimated Koc value suggests that oleandrin is expected to have low mobility in soil.

/SIGNS AND SYMPTOMS/ In poisoning by oleander, mydriasis characteristically accompanies vertigo, convulsions, coma, and bradycardia. /Oleander/

/CASE REPORTS/ About 6 hr after a meal which included an undefined amount of snails collected under a plant of Nerium oleander, a 77-year-old woman with permanent atrial fibrillation (AF) documented for over 5 years, presented with bradycardia associated with gastrointestinal and neurological symptoms due to oleandrin poisoning. Laboratory findings showed a serum digoxin level of 7.8 ng/mL (therapeutic range: 0.5-2.0 ng/mL), although the patient had never taken digoxin. The ECG surprisingly showed sinus rhythm at 96 bpm with 2:1 atrioventricular block, and repolarization abnormalities suggestive of digitalis effect (Panel A). In the following days, with the progressive reduction of oleandrin serum concentration, the patient showed an improvement of symptoms and the ECG showed the transition from sinus rhythm to an atypical atrial flutter (Panel B), and finally to AF. Oleandrin is a toxic cardiac-glycoside-like that can induce tachy (atrial and ventricular ectopic arrhythmias) and bradyarrhythmias (sinus bradycardia, sinoatrial and atrioventricular blocks). This is the first report of oleandrin poisoning associated with cardioversion of a very long-lasting AF. The possible antiarrhythmic activity of oleandrin appeared to be dose-dependent as suggested by the finding that with the progressive reduction of its serum concentration there was a gradual desynchronization of the atrial electrical activity.

/CASE REPORTS/ Nerium oleander L., is a potentially lethal plant, since it has cardiac glycosides. However, numerous researches of its extracts have been performed against cancer cell lines in recent literature. This contradiction leads to misinterpretation and induces the prevalence of intoxication or fatal cases. This case is associated with an oleander-poisoned patient, who was admitted to the Emergency unit 20 hours after the first dose, and 8 hours after the second dose ... She had decided to /self-medicate/ for her Hashimoto's thyroiditis and malignant thyroid disease ... Oleandrin was detected in the urine at a concentration of 3.2 ng/mL and in the serum at a concentration of 8.4 ng/mL by chromatographic analysis at the time of admission. ...

/CASE REPORTS/ Nerium oleander is a very popular urban ornamental plant in Europe, but it is also extremely dangerous because it contains several types of glycosides, accidental ingestion of which can cause cardiac arrhythmias and even death ... This report concerns the discovery of the bodies of 2 young people, a man and a woman, in a forest in conditions of extreme malnutrition. Medicolegal investigations showed neither pathologic nor traumatic causes of death, but the presence of vegetal remains in the stomach was noticed. A common toxicological analysis resulted negative, but the implementation of more detailed investigations showed the presence of digoxin in the blood of both cadavers, excluding the possibility of a pharmaceutical provenience of digoxin, this laboratory result was interpreted as evidence of ingestion of oleander, which contains oleandrine, the cross reaction of which with digoxin is widely described in the literature. Identification of the 2 subjects, which occurred after 4 years, strengthened the hypothesis of accidental poisoning by oleander because it was ascertained that the 2 young people were vegans ...

Found in Nerium oleander L., Apocynaceae (Laurier rose); Used as a cardiotonic and diuretic; [Merck Index] Oleander is used as rat poison; [HSDB] Active principle of the oleander plant used formerly in rodenticides and insecticides; Used currently in pharmaceutical products; [IARC]

Farming (Pesticides) [Category: Industry]

MEDICATION

Oleandrin is a plant toxin found in Oleander (Nerium oleander). (L1253)

Use in cosmetics is prohibited

Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander) are potentially lethal plants after ingestion. Poisoning by these plants is a common toxicological emergency in tropical and subtropical parts of the world .... All parts of these plants are toxic, and contain a variety of cardiac glycosides including neriifolin, thevetin A, thevetin B, and oleandrin. Ingestion of either oleander results in nausea, vomiting, abdominal pain, diarrhoea, dysrhythmias, and hyperkalemia. ...

Oleander (Nerium oleander) is an oranamnetal evergreen shrub ... used as a freeway median divider in warmer /US/ states, such as California ...

Scientific Name: Cascabela thevetia or Thevetia peruviana (previously T. neriifolia); Common Name: Yellow oleander. /From table/